Umeclidinium

FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in 1 second. BL was the mean of the values measured 23 hour and 24 hour after dosing prior to Day 1 (ie. after the last open label \[OL\] tiotropium dosing and prior to the randomized dose). Change from BL is defined as the post-BL value minus the BL value. Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained at 23 and 24 hours after dosing on Day 84 (at Week 12 + 1 day). Analysis performed using a mixed repeated measures model (MMRM) with covariates of treatment, BL, center group, 24 hour subset flag, Day, Day by BL and Day by treatment interactions. ITT Population is defined as participants who received at least one dose of randomized study medication in the treatment period. Only those participants with data available at the specified time point were included in the analysis.

FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained 23 and 24 hours after dosing on Day 84 (Week 12). Trough FEV1 measurements were taken electronically by spirometry on Days 2, 28, 56, 84 and 85. Baseline trough FEV1 is the mean of the two assessments made -30 and -5 minutes (min) pre-dose on Day 1. Change from baseline was calculated as the trough FEV1 value on Day 85 minus the BL value. Analysis performed using a repeated measures model with covariates of treatment, baseline FEV1, centre group, 24 hour subset flag, Day, Day by baseline and Day by treatment interactions. The least squares mean changes are presented here.

FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Weighted mean is calculated from the pre-dose FEV1 and post-dose FEV1 measurements at 5 and 15 minutes and 1, 3, 6, 9, 12 (pre-evening dose), 13, 15, 18, 23, and 24 hours after the morning dose. Change from Baseline was calculated as the value at Day 84 minus the value at Baseline. Analysis was performed using an analysis of covariance of treatment, Baseline (mean of the two assessments made 30 minutes and 5 minutes pre-dose on Day 1), and smoking status. par.=participants.

FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 measurements were taken electronically by spirometry on Days 2, 28, 56, 84, 112, 140, 168, and 169. Baseline is defined as the mean of the assessments made 30 minutes (min) pre-dose and 5 min pre-dose on Treatment Day 1. Trough FEV1 is defined as the mean of the FEV1 values obtained at 23 and 24 hours (hr) after the previous morning's dosing (ie., trough FEV1 on Day 169 is the mean of the FEV1 values obtained 23 and 24 hr after the morning dosing on Day 168). Change from Baseline at a particular visit was calculated as the trough FEV1 value at that visit minus the Baseline value. Analysis was performed using a repeated measures model with covariates of treatment, Baseline (mean of the two assessmentsmade 30 min and 5 min pre-dose on Day 1), smoking status, center group, day, and day by Baseline and day by treatment interactions.

A response rate is defined as percentage of participants who achieved at least 30 percent decrease from Baseline in gravimetric sweat production at Day 29. Baseline was latest assessment prior to first dosing. A response rate of greater than 50 percent was considered to be clinically meaningful (greater than 50 percent of participants achieving at least 30 percent decrease from Baseline in gravimetric sweat production at Day 29). The posterior probability that response rate in sweat production is greater than 50 percent was analyzed. The evaluation was performed using Bayesian analysis, in which latest pre-dose value was used as Baseline.

Percentage of participants at Day 29 post-treatment with at least a 30 percent reduction from Baseline in sweat production measured by gravimetry. Participants remained at rest for at least 20-30 min before the measurements in order to reduce external interference. The latest pre-dose value was considered as Baseline value. The summary of percentage of participants from both the cohorts with at least 30 percent reduction from Baseline in sweat production was presented for the average of both palms.

Pharmacokinetic blood sampling was done at the following time points: Day 12 (pre-dose), Day 13 (pre-dose), Day 14 (pre-dose), Day 15 (3 hours \[h\], 6 h, 9 h, 10 h, 12 h, 16 h, and 24 h following the Day 14 dose), Day 16 (36 h and 48 h following the Day 14 dose). Approximately 3 ml of blood was taken at each timepoint. Mean and standard deviation of the umeclidinium concentration was reported. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

Pharmacokinetic blood sampling was done at Day 14 (pre-dose), Day 15 (3 h, 6 h, 9 h, 10 h, 12 h, 16 h, and 24 h following the Day 14 dose), Day 16 (36 h and 48 h following the Day 14 dose). Cmax and Ctau was determined directly from the concentration-time data.

Pharmacokinetic blood sampling was done at Day 14 (pre-dose), Day 15 (3 h, 6 h, 9 h, 10 h, 12 h, 16 h, and 24 h following the Day 14 dose), Day 16 (36 h and 48 h following the Day 14 dose). Tmax was determined directly from the concentration-time data.

Pharmacokinetic blood sampling was done at Day 14 (pre-dose), Day 15 (3 h, 6 h, 9 h, 10 h, 12 h, 16 h, and 24 h following the Day 14 dose), Day 16 (36 h and 48 h following the Day 14 dose). Derivation of lambda-Z was planned. However, the parameter could not be derived for any of the participant included in the study because of insufficient data in the elimination phase (\< 3 data points, coefficient of determination (R\^2) was not adequate).

Pharmacokinetic blood sampling was done at Day 14 (pre-dose), Day 15 (3 h, 6 h, 9 h, 10 h, 12 h, 16 h, and 24 h following the Day 14 dose), Day 16 (36 h and 48 h following the Day 14 dose). Derivation of t1/2 was planned. However, the parameter could not be derived for any of the participant included in the study because of insufficient data in the elimination phase (\< 3 data points, coefficient of determination (R\^2) was not adequate).

Pharmacokinetic blood sampling was done at Day 14 (pre-dose), Day 15 (3 h, 6 h, 9 h, 10 h, 12 h, 16 h, and 24 h following the Day 14 dose), Day 16 (36 h and 48 h following the Day 14 dose). Calculated using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid. Geometric mean of log-transformed values of AUC were reported.

Pharmacokinetic blood sampling was done at Pre-dose, 3h, 6h, 9h, 10h, 12h, 16h, 24h, 36h, 48h of current study (202093), pre-dose, 10, 20, 30, 32, 35, 45 minute, 1h, 2h, 4h, 6h, 8h, 12h, 16h, 24h, 36h, 48h for study AC4112008, and Pre-dose, 2h, 4h, 5h, 6h, 8h, 8.5h, 9h, 9.5h, 10h, 11h, 12h, 13h, 14h, 16h, 24h, 30h, 36h, 48h, 72h for study number LHH117157. Plasma umeclidinium concentration time data following administration to axilae of hyperhidrosis participants from the current study (202093) were pooled with data from the occluded axilla cohort from study LHH117157 and the IV infusion data from study AC4112008 in order modify the existing population PK model for dermal umeclidinium. Plasma concentration-time data was subjected to nonlinear mixed effects modelling using the program NONMEM to develop a population PK model. The data for V1 and V2 was reported as mean (estimate) with relative standard error (RSE). RSE= (Standard error of the estimate/ Final parameter estimate) X 100.

Pharmacokinetic blood sampling was done at Pre-dose, 3h, 6h, 9h, 10h, 12h, 16h, 24h, 36h, 48h of current study (202093), pre-dose, 10, 20, 30, 32, 35, 45 minute, 1h, 2h, 4h, 6h, 8h, 12h, 16h, 24h, 36h, 48h for study AC4112008, and Pre-dose, 2h, 4h, 5h, 6h, 8h, 8.5h, 9h, 9.5h, 10h, 11h, 12h, 13h, 14h, 16h, 24h, 30h, 36h, 48h, 72h for study number LHH117157. Plasma umeclidinium concentration time data following administration to axilae of hyperhidrosis participants from the current study (202093) were pooled with data from the occluded axilla cohort from study LHH117157 and the IV infusion data from study AC4112008 in order modify the existing population PK model for dermal umeclidinium. Plasma concentration-time data was subjected to nonlinear mixed effects modelling using the program NONMEM to develop a population PK model. The data for CL and Q was reported as mean (estimate) with RSE. RSE= (Standard error of the estimate/ Final parameter estimate) X 100.

Pharmacokinetic blood sampling was done at Pre-dose, 3h, 6h, 9h, 10h, 12h, 16h, 24h, 36h, 48h of current study (202093), pre-dose, 10, 20, 30, 32, 35, 45 minute, 1h, 2h, 4h, 6h, 8h, 12h, 16h, 24h, 36h, 48h for study AC4112008, and Pre-dose, 2h, 4h, 5h, 6h, 8h, 8.5h, 9h, 9.5h, 10h, 11h, 12h, 13h, 14h, 16h, 24h, 30h, 36h, 48h, 72h for study number LHH117157. Plasma umeclidinium concentration time data following administration to axilae of hyperhidrosis participants from the current study (202093) were pooled with data from the occluded axilla cohort from study LHH117157 and the IV infusion data from study AC4112008 in order modify the existing population PK model for dermal umeclidinium. Plasma concentration-time data was subjected to nonlinear mixed effects modelling using the program NONMEM to develop a population PK model. The data for Ka was reported as mean (estimate) with RSE. RSE= (Standard error of the estimate/ Final parameter estimate) X 100.

Pharmacokinetic blood sampling was done at Pre-dose, 3h, 6h, 9h, 10h, 12h, 16h, 24h, 36h, 48h of current study (202093), pre-dose, 10, 20, 30, 32, 35, 45 minute, 1h, 2h, 4h, 6h, 8h, 12h, 16h, 24h, 36h, 48h for study AC4112008, and Pre-dose, 2h, 4h, 5h, 6h, 8h, 8.5h, 9h, 9.5h, 10h, 11h, 12h, 13h, 14h, 16h, 24h, 30h, 36h, 48h, 72h for study number LHH117157. Plasma umeclidinium concentration time data following administration to axilae of hyperhidrosis participants from the current study (202093) were pooled with data from the occluded axilla cohort from study LHH117157 and the IV infusion data from study AC4112008 in order modify the existing population PK model for dermal umeclidinium. Plasma concentration-time data was subjected to nonlinear mixed effects modelling using the program NONMEM to develop a population PK model. The data for FA and F2 (FIXED) was reported as mean (estimate) with RSE. RSE= (Standard error of the estimate/ Final parameter estimate) x 100.

Pharmacokinetic blood sampling was done at Pre-dose, 3h, 6h, 9h, 10h, 12h, 16h, 24h, 36h, 48h of current study (202093), pre-dose, 10, 20, 30, 32, 35, 45 minute, 1h, 2h, 4h, 6h, 8h, 12h, 16h, 24h, 36h, 48h for study AC4112008, and Pre-dose, 2h, 4h, 5h, 6h, 8h, 8.5h, 9h, 9.5h, 10h, 11h, 12h, 13h, 14h, 16h, 24h, 30h, 36h, 48h, 72h for study number LHH117157. Plasma umeclidinium concentration time data following administration to axilae of hyperhidrosis participants from the current study (202093) were pooled with data from the occluded axilla cohort from study LHH117157 and the IV infusion data from study AC4112008 in order modify the existing population PK model for dermal umeclidinium. Plasma concentration-time data was subjected to nonlinear mixed effects modelling using the program NONMEM to develop a population PK model. The data for ALAG1 was reported as mean (estimate) with RSE. RSE= (Standard error of the estimate/ Final parameter estimate) x 100.

AE was defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE include AEs those result in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

Single 12-lead ECGs was obtained at Day 1, Day 14 and Day 28 during the study. The standard ECG criteria of potential clinical importance were 1) absolute QTc Interval, \> 450 milliseconds (msec), 2) absolute PR Interval, \<110 msec, 3) absolute QRS Interval, \< 75 msec and 4) increase from baseline in QTc \> 60 msec. The number of participants with potentially clinically significant ECG findings at any visit were reported.

The clinical chemistry parameters analyzed were albumin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, bicarbonate, blood urea nitrogen, calcium, chloride, creatinine, gamma glutamyl transferase, glucose, potassium, sodium, total and direct bilirubin, total protein, uric acid. Only those parameters for which at least one value of potential clinical importance was reported are summarized. The number of participants with potential clinical important clinical chemistry findings at any visit were reported.

The hematology parameters analyzed were basophils, eosinophils, erythrocyte mean corpuscular hemoglobin concentration, erythrocyte mean corpuscular hemoglobin, erythrocyte mean corpuscular volume, erythrocytes, hematocrit, hemoglobin, leukocytes, lymphocytes, monocytes, neutrophils, platelets, and reticulocytes. Only those parameters for which at least one value of potential clinical importance was reported are summarized. The number of participants with potential clinical important hematology findings at any visit were reported.

The urinalysis parameters analyzed were specific gravity, pH, glucose, protein, blood and ketones by dipstick, microscopic examination. Only those parameters for which at least one value of potential clinical importance was reported are summarized. The number of participants with potential clinical important urinalysis findings at any visit were reported.

The potential clinical importance ranges (low and high) of the vital sign parameters were for systolic blood pressure (\<85 and \>160 millimeter of mercury \[mmHg\]), diastolic blood pressure (\<45 and \>100 mmHg) and heart rate (\<40 and \>110 beats per minute). Only those parameters for which at least one value of potential clinical importance was reported are summarized. The number of participants with potential clinical important vital parameter findings at any visit were reported.

The investigator or designated evaluator assessed skin tolerability at each visit using the 5-point tolerability scale. Tolerability of the topical application was assessed and scored as, 0- none (no evidence of local intolerance), 1-mild (minimal erythema and/or edema, slight glazed appearance), 2-moderate (definite erythema and/or edema with peeling and/or cracking but needs no adaptation of posology), 3-severe (erythema, edema glazing with fissures, few vesicles or papules), 4- very severe (strong reaction spreading beyond the treated area, bullous reaction, erosions).

Blood sample will be collected for PK assessment including maximum observed plasma concentration (Cmax).

Blood sample will be collected for PK assessment including time to Cmax (tmax).

Blood sample will be collected for PK assessment including area under the plasma concentration-time curve (AUC) from time 0 to the last quantifiable sample (AUC0-last), AUC from time zero to 12 hrs or 24 hrs (AUC0-12 and AUC0-24, respectively), AUC from time zero to time infinity \[AUC (0-infinity)\].

Blood sample will be collected for PK assessment including apparent terminal phase half-life (t1/2).

Compartmental modeling may be conducted to characterize the absorption rate constants.

Compartmental modeling may be conducted to characterize the elimination rate constants.